Vehicles are essential components of formulations for administration of biologically active substances (BAS), such as drugs. The vehicle functions as a carrier for the BAS. The BAS is typically either dissolved dispersed, or suspended in the vehicle to form a solution, an emulsion, or a suspension. The physical form of a BAS-loaded vehicle may be a liquid, a gel, a semisolid, a paste, or a solid.
A BAS, and a vehicle containing a BAS, may be in any physical state for administration to a subject, such as by oral, topical, rectal, vaginal, or parenteral routes. Typically, for parenteral administration, solid forms of BAS must be rendered into a liquid or semisolid form, or suspended in a liquid vehicle, in order to be capable of being injected. Liquid forms of BAS also typically require a vehicle because the undiluted form of the BAS is generally too toxic to be administered directly. An undiluted BAS may irritate the site of injection. Diluting the BAS with a vehicle reduces the irritation. Also, diluting a BAS facilitates the administration of very small quantities of a BAS. These considerations are generally less important with application to the environment or with administration to a subject by other than parenteral routes. However, even with such non-parenteral administration, in many situations one or more of these considerations may be important.
The physiochemical properties of a vehicle are important in determining the release characteristics of the administered BAS. Typically pharmacological formulations containing a hydrophilic vehicle rapidly release their BAS into the body. In contrast, hydrophobic vehicles retard the contact of a BAS with aqueous body fluids and so can be used to control the release of a BAS from the site of administration. For many administration indications, such delayed release of a BAS from the site of administration is desired.
A vehicle should be pharmacologically inert, that is it does not produce a biochemical response by a body in which it is administered. The vehicle should also be non-irritating and non-toxic in the amounts administered. It should be stable and should not compromise the stability of the BAS.
An ideal vehicle has several additional characteristics. Ideally, a vehicle for parenteral use has good syringeability and injectability if the formulation is to be administered by a syringe. Ideally, the viscosity of a vehicle should be capable of being tailored so that a less viscous vehicle may injected as a liquid by a syringe, for example with parenteral administration, or may be applied by a spray, such as for topical or environmental applications. Conversely, a more viscous vehicle may be desirable to be smeared or applied in a gel or paste form, such as for topical administration or environmental application. Further, an ideal vehicle should be capable of being tailored to provide a range of hydrophilicity or hydrophobicity. Modification of viscosity and hydrophobicity or hydrophilicity of a vehicle permits a formulator to produce a composition having desired release characteristics, either an immediate or controlled release.
Water is the most commonly used vehicle for parenteral administration of BAS. However, it is unsuitable for controlled delivery of BAS because a drug dissolved in a water vehicle is immediately released into aqueous bodily fluids. Vehicles used for controlled delivery of BAS are typically fixed vegetable oils, polymer-based aqueous gels, and polymer-based water immiscible gels.
The following patents, each of which is incorporated herein by reference, disclose vehicles for controlled delivery of BAS. Maulding, U.S. Pat. No. 4,297,353, discloses a glyceride vehicle comprising a glycerol ester of a vegetable fatty acid. Carlsson, U.S. Pat. No. 6,117,857, discloses a vehicle of an admixture of a galactolipid extracted from plant material and a polar solvent, such as water, glycerol, ethanol, propylene glycol, polyethylene glycol, polypropylene glycol, glycofurol, methylpyrrolidone, or transcutol. Brooks, U.S. Pat. No. 5,352,662, discloses a vehicle for extended release formulations comprising a biocompatible hydrophobic vehicle such as sesame seed oil and a polyglycerol ester such as diglycerol tetrastearate. Tipton, U.S. Pat. No. 5,747,058, discloses a high viscosity liquid controlled delivery system in which the vehicle is a combination of sucrose acetate isobutyrate and a solvent which may be ethanol, dimethylsulfoxide, ethyl lactate, benzyl alcohol, triacetin, 2-pyrrolidone, N-methylpyrrolidone, propylene carbonate, or glycofurol. Wicks, U.S. Pat. No. 6,001,822, discloses an antiparasitic formulation in a vehicle of 50% to 95% sesame oil with the remainder ethyl oleate. Hausheer, U.S. Pat. No. 5,958,937, discloses a vehicle for producing a formulation of poorly water-soluble camptothecin and its analogues. The vehicle of Hausheer is N-methyl-2-pyrrolidinone with additives such as surfactant, polyethylene glycol, ethyl alcohol, and benzyl alcohol.
These and other prior art vehicles fail to provide the essential and ideal characteristics of a vehicle. The water based vehicles are not suitable for controlled release of a BAS. Like water based vehicles, aqueous gel vehicles are not suitable for sustained release of BAS, especially for very water-soluble BAS. The stability of a BAS is often compromised by the presence of fixed vegetable oils. A significant need exists for a vehicle that overcomes these and other disadvantages of currently available vehicles.
Esters of citric acid have been incorporated in a variety of compositions. Weil, U.S. Pat. No. 5,047,166, incorporated herein by reference, discloses several uses of salts of citric acid esters. The invention disclosed in Weil utilizes citric acid ester salts for their usefulness in providing a smooth and creamy feel to the skin. Weil further discloses that citric acid ester salts have been used in treating clothes, in food technology to retard rancidity and improve moisture retention, and have been employed as constituents of shampoos, deodorants, and soaps.
A major use of citric acid esters is as a plasticizer for polymers used as coatings for tablets and other oral forms of medication, such as capsules and caplets. The citric acid ester plasticizers are added to a solution or dispersion of a polymer and reduce the intermolecular attractions between polymeric chains. In so doing, the citrate ester increases the free volume of the polymer, allowing it to move more freely and so increase the polymer's workability, flexibility, and distensibility. Citric acid esters have also been used as plasticizers in film coatings, in toys for toddlers and infants, in plastic blood bags, and in plastic tubing used as catheters.
To date, there has been no disclosure of the use of citric acid esters as a vehicle for a BAS, such as in a pharmaceutical formulation or in a formulation for application to the environment.